The molecular targets for vitreoretinopathy and uveitis (intraocular inflammation) are poorly understood. This proposal builds on our exciting discovery of a calcium-activated protease, CAPN5 (calpain-5), as the cause of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV), and that CAPN5 processes PDGFB signaling. CAPN5 is the first nonsyndromic uveitis gene, and makes possible a highly innovative molecular-genetic approach for mechanism-based therapies for inflammation induced by photoreceptor degeneration. Photoreceptors express CAPN5, and an hCAPN5-R243L gain of function mutation in mice shows all the phenotypes of human ADNIV disease. The retina photoreceptors might be particularly sensitive to mutations in CAPN5, because high intracellular calcium is necessary and sufficient to regulate dark adaptation in photoreceptors. Our long-term goals are to find better and more specific treatments for inflammatory vitreoretinopathy. Our objective is to use in vitro and in vivo cell culture and mouse models to determine the mechanisms responsible for controlling activity of CAPN5. We will also investigate how uncontrolled CAPN5 activity leads to aberrant signaling of one of its substrates, platelet-derived growth factor B (PDGFB), and how this signaling results in the subsequent ADNIV phenotypes. Our central hypothesis is that an uncontrolled, calcium-activated CAPN5 pathway leads to ADNIV retinal degeneration and uveitis through aberrant PDGFB signaling. By creating a new mouse model we will be able to identify new therapeutic targets. Our specific aims are to (1) Dissect the ADNIV CAPN5 autoproteolysis effect in cells, (2) Determine if ADNIV CAPN5 hyperactively cleaves PDGFB to upregulate signaling, and (3) Test if PDGFB loss rescues the ADNIV phenotype in a preclinical mouse model. Impact. We expect to gain not only a better understanding of calpain activity and the role PDGFB plays in eye disease, but also to identify new therapeutic targets that may be applicable to many eye diseases. Our work should help determine the role of PDGFB signaling in ADNIV and other vitreoretinal degenerative diseases.